Paclitaxel is a widely used chemotherapeutic agent for treating a range of carcinomas. The clinical material is formulated in Cremophor® EL/ethanol, and is diluted with buffer prior to administration. There are many reports in the literature describing attempts to improve the formulation of paclitaxel using micelles, liposomes or emulsions.1, 15, 16, 17 In almost all cases, however, it is clear from the reported pharmacokinetic data that while these carriers formulate paclitaxel, they do not act as true delivery vehicles in vivo since the drug rapidly partitions out of the carrier with half lives on the order of minutes. One exception appears to be a formulation known as NK105.2 NK105 is paclitaxel formulated in micelles comprised of poly(ethyleneglycol)-poly(aspartic acid) in which the carboxyl groups are capped with 4-phenylbutanol.
Many attempts have also been made to produce functional lipophilic paclitaxel prodrugs to improve the performance of paclitaxel or to address formulations issues associated with the drug. These include conjugates with phospholipids3, 4, cholesterol5, α-bromo fatty acids6, 7, oleic acid8, 9, fullerene10 and docosahexanoic acid11. These prodrugs were formulated in lipid vehicles, such as liposomes3, 7, 10, oil emulsions8, 9 or micelles5, 6, 11. In addition, WO2006/014626 discloses conjugates of paclitaxel and other drugs with hydrophobic moieties which may exist in particulate form. Most of these reports claim improved efficacy over paclitaxel in in vivo models, however, in most cases they either provide no information on plasma drug elimination or present data focusing on the terminal drug elimination phase rather than the early distribution phase. Drug elimination information during the first 24 h after administration is the period of most significant interest from a tumor delivery perspective due to the enhanced permeability and retention (EPR) phenomenon observed with particulate carriers, including micelles and nanoparticles.
The invention is exemplified by a series of lipophilic paclitaxel prodrugs and associated micellar/nanoparticle formulations. Particulate delivery vehicles with prolonged circulation half lives are described where the release of drug is modulated by manipulating the degree of a lipid anchor hydrophobicity and the lability of the prodrug cross-linkers. The efficacy of the prodrugs in vivo are shown to be dependant on the nature of the linkage and the relative partitioning rate of the lipid anchor.
Many chemotherapeutic treatment regimes involve multiple drugs. Many drug combinations act synergistically at appropriate ratios, but antagonistically at other ratios in cell based studies. When these findings are applied to in vivo studies different pharmacokinetic behaviors of the individual drugs when administered in a conventional aqueous based cocktail, alter the administered ratio. This problem has been solved by using particulate delivery vehicles designed to coordinate drug delivery and release as described in PCT publication WO03/028696. The present invention offers an improvement that facilitates control in compositions that include paclitaxel and its analogs, as one or more additional antineoplastic agents can be formulated to mimic the pharmacokinetics of the taxane composition.